{"product_id":"anito-cel-car-t-cell-therapy-for-relapsed-or-refractory-multiple-myeloma-a-patient-guide-to-the-phase-1-study","title":"Anito-cel CAR T-Cell Therapy for Relapsed or Refractory Multiple Myeloma: A Patient Guide to the Phase 1 Study","description":"\u003cp\u003eIn a phase 1 clinical trial, 38 patients with heavily pretreated relapsed or refractory multiple myeloma received anito-cel, an investigational BCMA-directed CAR T-cell therapy. All 38 patients (100%) had a response, 79% achieved a complete response, and the median progression-free survival was 30.2 months. Serious neurological side effects and severe cytokine release syndrome were rare, and no cases of parkinsonism, Guillain-Barré syndrome, or colitis occurred.\u003c\/p\u003e\n\n\u003ch1\u003eAnito-cel CAR T-Cell Therapy for Relapsed or Refractory Multiple Myeloma: A Patient Guide to the Phase 1 Study\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#what-is\"\u003eWhat Is Anito-cel and How Does It Work?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#methods\"\u003eHow the Study Was Conducted\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#patients\"\u003eWho Were the Patients in This Study?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#safety\"\u003eKey Safety Findings\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#efficacy\"\u003eKey Efficacy Findings: How Well Did the Treatment Work?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#product\"\u003eHow Anito-cel Behaves in the Body\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#lab\"\u003eLaboratory Comparison: ddBCMA vs. Dual-VHH Binders\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eClinical Implications: What This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations: What the Study Could Not Prove\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Next Steps\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn a phase 1 study, 38 patients with heavily pretreated relapsed or refractory multiple myeloma received anito-cel, an investigational BCMA-directed CAR T-cell therapy.\u003c\/li\u003e\n\u003cli\u003eAll 38 patients (100%) had a response, 79% achieved a complete response, and median progression-free survival was 30.2 months.\u003c\/li\u003e\n\u003cli\u003eSerious neurological side effects and severe cytokine release syndrome were rare; no cases of parkinsonism, Guillain-Barré syndrome, or colitis occurred.\u003c\/li\u003e\n\u003cli\u003eAnito-cel is investigational and not approved; the recommended phase 2 dose was 100×10⁶ CAR+ T cells, now being tested in the iMMagine-1 trial.\u003c\/li\u003e\n\u003cli\u003eThis phase 1 study was not designed to prove one treatment is better than another, and longer follow-up is needed to assess durability and long-term safety.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eMultiple myeloma is a cancer of plasma cells, which are immune cells that live in the bone marrow. When the disease comes back after treatment (relapsed) or stops responding to treatment (refractory), patients need new options.\u003c\/p\u003e\n\n\u003cp\u003eB-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapies have improved outcomes for patients with relapsed or refractory multiple myeloma. BCMA is a protein found on the surface of myeloma cells. CAR T-cell therapy is a treatment in which a patient's own immune T cells are collected, genetically modified to recognize a specific target, and then returned to the patient.\u003c\/p\u003e\n\n\u003cp\u003eSome patients remain disease-free beyond 5 years after treatment with ciltacabtagene autoleucel (cilta-cel), a currently approved BCMA-directed CAR T-cell therapy. This finding suggests that a potential cure may be possible for some patients.\u003c\/p\u003e\n\n\u003cp\u003eHowever, rare but irreversible non–immune effector cell–associated neurotoxicity syndrome (ICANS) neurotoxic effects have been reported with cilta-cel. These include parkinsonism (a movement disorder with tremor and stiffness) and Guillain–Barré syndrome (a condition in which the immune system attacks nerves, causing weakness). Immune effector cell–associated enterocolitis (inflammation of the intestines caused by immune cells) has also been reported.\u003c\/p\u003e\n\n\u003cp\u003eThe pathophysiological features of these toxic effects remain poorly understood. So do the mechanistic differences that explain why these toxic effects are relatively absent with other BCMA-directed CAR T-cell therapies.\u003c\/p\u003e\n\n\u003cp\u003eCurrently approved CD19 CAR T cells for lymphoma all share the same FMC63-based single-chain variable fragment binder. In contrast, cilta-cel, idecabtagene vicleucel (ide-cel), and anitocabtagene autoleucel (anito-cel) each use different BCMA binders. A binder is the part of the CAR that recognizes and attaches to the target protein.\u003c\/p\u003e\n\n\u003cp\u003eUnique binder attributes influence signal strength and downstream T-cell function. These attributes include the association–dissociation kinetics of antigen–receptor interactions, meaning how quickly the binder attaches to and releases from its target. These differences may contribute to the differing clinical profiles observed across products.\u003c\/p\u003e\n\n\u003cp\u003eAnito-cel (formerly called CART-ddBCMA) is an investigational, autologous BCMA-directed CAR T-cell therapy. \"Autologous\" means the cells come from the patient's own body. Anito-cel uses a small (8 kDa), de novo–generated d-domain binder (ddBCMA). This binder is designed to fold rapidly and to bind with a fast off-rate. A fast off-rate means that once the binder attaches to BCMA, it releases from it quickly.\u003c\/p\u003e\n\n\u003cp\u003eThe ddBCMA binder is also designed to limit the antigen-independent aggregation that has been observed with conventional CAR binders that are antibody-based. Antigen-independent aggregation means the binders clump together even when the target protein is not present.\u003c\/p\u003e\n\n\u003cp\u003eSufficiently fast off-rates can promote improved signaling. The signaling is strong enough to kill the tumor cells but minimizes cytokine release and activation-induced cell death. This happens because rapid antigen dissociation and rebinding occur without sustained binding.\u003c\/p\u003e\n\n\u003cp\u003eProlonged engagement between CAR T cells and antigen-expressing cells can lead to a state of functional T-cell exhaustion. This exhaustion reduces serial killing, which is the destruction of multiple tumor cells by a single CAR T cell. It also leads to high-intensity cytokine production.\u003c\/p\u003e\n\n\u003cp\u003eThis article reports safety and efficacy results from the first-in-human phase 1 study evaluating anito-cel in patients with relapsed or refractory multiple myeloma. The researchers also evaluated the in vitro characteristics of the anito-cel binder. \"In vitro\" means in laboratory experiments outside the body. The goal was to explore properties that may contribute to the clinical safety profile observed to date.\u003c\/p\u003e\n\n\u003ch2 id=\"what-is\"\u003eWhat Is Anito-cel and How Does It Work?\u003c\/h2\u003e\n\n\u003cp\u003eAnito-cel is a type of CAR T-cell therapy. The treatment starts with collecting a patient's own T cells. These cells are then genetically modified in a laboratory so they carry a chimeric antigen receptor (CAR) on their surface.\u003c\/p\u003e\n\n\u003cp\u003eThe CAR used in anito-cel is directed at BCMA, a protein found on myeloma cells. The binder portion of this CAR is called ddBCMA. It is a small protein fragment, only 8 kDa in size, that was generated de novo, meaning it was designed from scratch rather than derived from an antibody.\u003c\/p\u003e\n\n\u003cp\u003eThe ddBCMA binder has two key design features:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eFast off-rate:\u003c\/strong\u003e Once the binder attaches to BCMA, it releases quickly. This allows the CAR T cell to move on and attack other tumor cells.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLimited aggregation:\u003c\/strong\u003e The binder is designed not to clump together when its target is absent. Conventional antibody-based CAR binders can clump together without antigen, which may cause unwanted activation.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese design features are intended to allow the CAR T cells to kill tumor cells effectively while producing fewer inflammatory cytokines. Cytokines are chemical signals that immune cells release. Too many cytokines can cause serious side effects.\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow the Study Was Conducted\u003c\/h2\u003e\n\n\u003cp\u003eThis was a phase 1 study, which is the first stage of testing a new treatment in humans. The study evaluated anito-cel in eligible adults with relapsed or refractory multiple myeloma.\u003c\/p\u003e\n\n\u003cp\u003eTo be eligible, patients had to have received at least three previous lines of therapy. Those previous treatments had to include an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Alternatively, patients could be eligible if they had triple-class refractory disease, meaning their disease was refractory to all three classes of drugs.\u003c\/p\u003e\n\n\u003cp\u003eThe study included two components: dose escalation and dose expansion. Dose escalation means testing increasing doses to find the right one. Dose expansion means treating more patients at the chosen dose to learn more about safety and activity.\u003c\/p\u003e\n\n\u003cp\u003ePatients received anito-cel at one of two dose levels:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eDose level 1:\u003c\/strong\u003e 100×10\u003csup\u003e6\u003c\/sup\u003e CAR+ T cells\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDose level 2:\u003c\/strong\u003e 300×10\u003csup\u003e6\u003c\/sup\u003e CAR+ T cells\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe cells were given on day 0. Peripheral-blood samples were obtained at screening, on day 0, and at various time points after the infusion for correlative analyses.\u003c\/p\u003e\n\n\u003cp\u003eA standard 3+3 design was used to identify the recommended phase 2 dose. This means 6 patients were enrolled in each dose-level cohort. The size of the expansion cohort reflected clinical and operational considerations rather than formal statistical power. A cohort size of approximately 26 patients was deemed adequate to characterize safety and estimate preliminary activity at the recommended dose.\u003c\/p\u003e\n\n\u003cp\u003eThe study was funded by Arcellx and Kite, a Gilead company. Both companies contributed to the acquisition, analysis, and interpretation of the data. They also drafted and critically reviewed the manuscript and approved the decision to submit it for publication.\u003c\/p\u003e\n\n\u003cp\u003eThe primary end points were adverse events during the treatment period and establishment of the recommended phase 2 dose. An adverse event counted as part of the treatment period if it started on or after the first anito-cel infusion and continued until 90 days. Any adverse event occurring at any time that the investigator assessed as related to anito-cel also counted.\u003c\/p\u003e\n\n\u003cp\u003eSecondary end points were investigator-assessed best overall response and overall response, assessed according to the International Myeloma Working Group consensus criteria, and pharmacokinetics. Pharmacokinetics refers to how the treatment moves through and behaves in the body.\u003c\/p\u003e\n\n\u003cp\u003eExploratory end points were summarized descriptively. These included duration of response, time to response, time to progression, progression-free survival, overall survival, minimal residual disease (MRD) status, and manufacturing outcomes. MRD status refers to whether tiny amounts of cancer cells can still be detected. Correlative pharmacokinetic and pharmacodynamic analyses were also included.\u003c\/p\u003e\n\n\u003cp\u003eSubgroup analyses were performed in the efficacy-evaluable population. This population included all patients who received any dose (full or partial) of anito-cel and had a baseline disease assessment and at least one postbaseline disease assessment. Response and progression-free survival were also assessed according to the presence or absence of identified high-risk features. These features included extramedullary disease, a β\u003csub\u003e2\u003c\/sub\u003e-microglobulin level of at least 5.5 mg per liter, high-risk cytogenetics, high-risk cytogenetics inclusive of 1q gain, bone marrow plasma cells of at least 60%, and an age of 65 years or older.\u003c\/p\u003e\n\n\u003cp\u003eFor the preclinical assessment, the researchers compared the biophysical binding properties of the soluble protein versions of the ddBCMA binder used in anito-cel. The researchers also compared the dual variable heavy-chain domain of a heavy chain-only antibody (dual-VHH) BCMA binder used in cilta-cel. They used biolayer interferometry and size-exclusion chromatography for this comparison.\u003c\/p\u003e\n\n\u003cp\u003eCAR functional activity in vitro was assessed with research-grade ddBCMA or dual-VHH CAR T cells. These cells were generated under the same manufacturing conditions and CAR architecture. This approach allowed the researchers to assess binder effects independent of transmembrane and intracellular domains. CAR T cells were cultured either alone or with BCMA-expressing tumor cells. The researchers then assessed binding, cytotoxic activity, CAR T-cell proliferation, and cytokine release.\u003c\/p\u003e\n\n\u003cp\u003eFor the statistical analysis, data are presented as medians with ranges for continuous variables and as numbers with percentages for categorical variables. Estimates of response duration, progression-free survival, and overall survival were calculated by the Kaplan–Meier method and are reported with associated 95% confidence intervals. Because the study was not designed for hypothesis testing, confidence intervals are descriptive and were not adjusted for multiplicity.\u003c\/p\u003e\n\n\u003ch2 id=\"patients\"\u003eWho Were the Patients in This Study?\u003c\/h2\u003e\n\n\u003cp\u003eFrom January 6, 2020, to July 25, 2022, a total of 40 patients were enrolled and had successful manufacture of anito-cel. Two patients did not undergo infusion. One patient had an infection, and one patient had heart failure–induced hypoxia (low oxygen levels caused by heart failure). Both patients had an available cell product.\u003c\/p\u003e\n\n\u003cp\u003eDose level 1 was selected for the dose-expansion cohort. This decision was made because the safety and efficacy profiles were similar to those observed with dose level 2, and the manufacturing success was 100%.\u003c\/p\u003e\n\n\u003cp\u003eThe characteristics of the patients were similar in the two dose cohorts. The patients were representative of patients with heavily pretreated relapsed or refractory multiple myeloma.\u003c\/p\u003e\n\n\u003cp\u003eKey baseline characteristics of the 38 patients who received anito-cel:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eMedian age:\u003c\/strong\u003e 66 years (range, 44 to 76)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAge 65 or older:\u003c\/strong\u003e 20 patients (53%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMale:\u003c\/strong\u003e 23 patients (61%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eFemale:\u003c\/strong\u003e 15 patients (39%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eWhite race:\u003c\/strong\u003e 32 patients (84%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eBlack race:\u003c\/strong\u003e 4 patients (11%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAsian race:\u003c\/strong\u003e 1 patient (3%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eOther race:\u003c\/strong\u003e 1 patient (3%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eECOG performance-status score of 0:\u003c\/strong\u003e 12 patients (32%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eECOG performance-status score of 1:\u003c\/strong\u003e 26 patients (68%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe Eastern Cooperative Oncology Group (ECOG) performance-status score is assessed on a scale from 0 to 5. Higher scores indicate greater disability.\u003c\/p\u003e\n\n\u003cp\u003eHigh-risk prognostic features at baseline included:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eExtramedullary disease:\u003c\/strong\u003e 12 patients (32%). Extramedullary disease was defined as the presence of a non–bone-based plasmacytoma at the screening or baseline visit.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eBone marrow plasma cells of at least 60%:\u003c\/strong\u003e 12 patients (32%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eβ\u003csub\u003e2\u003c\/sub\u003e-microglobulin level of at least 5.5 mg per liter:\u003c\/strong\u003e 7 patients (18%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHigh-risk cytogenetic abnormality:\u003c\/strong\u003e 11 patients (29%). This was defined as the presence of del 17p, t(14;16), or t(4;14).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHigh-risk cytogenetic abnormality inclusive of 1q gain:\u003c\/strong\u003e 26 patients (68%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eOther important baseline characteristics:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eMedian number of previous lines of therapy:\u003c\/strong\u003e 4 (range, 3 to 14)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTriple-class–refractory disease:\u003c\/strong\u003e 38 patients (100%). This was defined as disease refractory to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePenta-drug–refractory disease:\u003c\/strong\u003e 26 patients (68%). This was defined as disease refractory to at least two unique immunomodulatory drugs, two unique proteasome inhibitors, and one anti-CD38 therapy.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePrevious autologous stem-cell transplantation:\u003c\/strong\u003e 28 patients (74%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePrevious BCMA-directed therapy:\u003c\/strong\u003e 1 patient (3%). This was defined as a BCMA-directed antibody–drug conjugate.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMedian time since diagnosis:\u003c\/strong\u003e 6.5 years (range, 1.5 to 14.9)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eBridging therapy:\u003c\/strong\u003e 28 patients (74%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eBridging therapy was limited to previously received agents, and no bispecific monoclonal antibody therapies were allowed. Of the 28 patients who received bridging therapy, 21 (75%) had an increase or no change in tumor burden. This was assessed on the basis of the percent change in the serum M-protein, urinary M-protein, or involved free light-chain level as a consequence of bridging therapy. Four patients (14%) had a decreased tumor burden, and 3 patients (11%) could not be evaluated.\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eKey Safety Findings\u003c\/h2\u003e\n\n\u003cp\u003eAmong the 38 patients who received anito-cel, with a median follow-up of 38.1 months, all 38 (100%) had at least one adverse event during the treatment period. This was the primary end point. A total of 37 patients (97%) had an adverse event of grade 3 or higher. Cytopenias were the most common. Cytopenias are low counts of blood cells. No grade 5 events occurred. A grade 5 event is a fatal event.\u003c\/p\u003e\n\n\u003cp\u003eOf the 32 patients evaluated in the dose level 1 cohort, 31 (97%) had an adverse event of grade 3 or higher.\u003c\/p\u003e\n\n\u003cp\u003eThe most common adverse events of any grade were:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eNeutropenia\u003c\/strong\u003e (low neutrophil count): 33 patients (87%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eThrombocytopenia\u003c\/strong\u003e (low platelet count): 26 patients (68%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAnemia\u003c\/strong\u003e (low red blood cell count): 24 patients (63%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHypophosphatemia\u003c\/strong\u003e (low phosphate levels): 18 patients (47%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eFatigue:\u003c\/strong\u003e 17 patients (45%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLymphopenia\u003c\/strong\u003e (low lymphocyte count): 15 patients (39%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHypokalemia\u003c\/strong\u003e (low potassium levels): 13 patients (34%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHypogammaglobulinemia\u003c\/strong\u003e (low levels of protective antibodies): 12 patients (32%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eConstipation:\u003c\/strong\u003e 10 patients (26%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDiarrhea:\u003c\/strong\u003e 10 patients (26%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDecreased appetite:\u003c\/strong\u003e 9 patients (24%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDizziness:\u003c\/strong\u003e 9 patients (24%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHeadache:\u003c\/strong\u003e 9 patients (24%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHypocalcemia\u003c\/strong\u003e (low calcium levels): 8 patients (21%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLeukopenia\u003c\/strong\u003e (low white blood cell count): 8 patients (21%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eNausea:\u003c\/strong\u003e 8 patients (21%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eAdverse events of special interest included cytokine release syndrome, ICANS, and grade 3 or higher infection.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCytokine release syndrome\u003c\/strong\u003e occurred in 36 patients (95%). This included 30 of 32 patients (94%) who received anito-cel at dose level 1. No patients who received anito-cel at dose level 1 had grade 3 cytokine release syndrome. One patient (17%) who received anito-cel at dose level 2 had grade 3 cytokine release syndrome. The median time to the onset of cytokine release syndrome was 2 days (range, 1 to 12). The median duration was 5 days (range, 1 to 9).\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eICANS\u003c\/strong\u003e occurred in 7 patients (18%) overall. This included 6 of 32 patients (19%) who received anito-cel at dose level 1. Five patients (16%) had grade 1 or 2 ICANS, and 1 patient (3%) had grade 3 ICANS. The median time to the onset of ICANS was 5 days (range, 3 to 7). The median duration was 4 days (range, 1 to 17).\u003c\/p\u003e\n\n\u003cp\u003eA total of 32 of 38 patients (84%) received tocilizumab, and 25 (66%) received dexamethasone for cytokine release syndrome, ICANS, or both. Tocilizumab and dexamethasone are medications used to manage these side effects.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eHypogammaglobulinemia\u003c\/strong\u003e was present in 6 patients (16%) as an ongoing medical history at the time of trial enrollment. Twelve patients (32%) had hypogammaglobulinemia during the treatment period after receiving anito-cel.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eInfection\u003c\/strong\u003e of any grade occurred in 21 patients (55%). Six patients (16%) had infection of grade 3 or higher. No grade 5 infections occurred.\u003c\/p\u003e\n\n\u003cp\u003eNo other adverse events of special interest occurred. Specifically, there were no cases of parkinsonism, cranial-nerve palsies, Guillain–Barré syndrome, or colitis. No second primary T-cell cancers occurred.\u003c\/p\u003e\n\n\u003cp\u003eSecondary primary myelodysplastic syndrome was reported in 3 of 38 patients (8%) as an adverse event. Myelodysplastic syndrome is a disorder in which the bone marrow does not make enough healthy blood cells. These events occurred in the context of disease progression and after exposure to cytotoxic chemotherapy. The investigators assessed the events as being unrelated to anito-cel.\u003c\/p\u003e\n\n\u003ch2 id=\"efficacy\"\u003eKey Efficacy Findings: How Well Did the Treatment Work?\u003c\/h2\u003e\n\n\u003cp\u003eAmong the 38 patients in the efficacy-evaluable population, all 38 (100%; 95% confidence interval [CI], 91 to 100) had a response. This was the secondary end point. A total of 30 patients (79%; 95% CI, 63 to 90) had a complete response. A total of 35 patients (92%; 95% CI, 79 to 98) had a very good partial response or better.\u003c\/p\u003e\n\n\u003cp\u003eIn analyses of exploratory end points:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eMedian duration of response:\u003c\/strong\u003e 29.1 months (95% CI, 15.8 to 35.1)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eOngoing response:\u003c\/strong\u003e 13 patients (34%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMedian progression-free survival:\u003c\/strong\u003e 30.2 months (95% CI, 16.6 to 36.2)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eProgression-free survival at 24 months:\u003c\/strong\u003e 57% (95% CI, 39 to 71)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMedian overall survival:\u003c\/strong\u003e Not reached (95% CI, 33.3 months to could not be evaluated)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eOverall survival at 36 months:\u003c\/strong\u003e 65% (95% CI, 46 to 79)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eAmong 28 patients who could be evaluated for MRD status, 25 (89%) had MRD-negative status at a sensitivity threshold of 10\u003csup\u003e−5\u003c\/sup\u003e. A total of 22 patients (79%) had MRD-negative status at a sensitivity threshold of 10\u003csup\u003e−6\u003c\/sup\u003e. A total of 20 patients (71%) had MRD-negative status with a confirmed complete response or better.\u003c\/p\u003e\n\n\u003cp\u003eSustained MRD-negative status for at least 12 months after the first MRD-negative assessment was observed in 13 of 18 patients (72%) in the efficacy-evaluable population who had sufficient follow-up.\u003c\/p\u003e\n\n\u003cp\u003eThe median follow-up for progression-free survival among patients in the efficacy-evaluable population was 33.9 months. This was calculated according to the reverse Kaplan–Meier method. Among patients who had a sustained MRD-negative status for at least 12 months, no patient had progression or death through 33 months after the anito-cel infusion.\u003c\/p\u003e\n\n\u003cp\u003eProgression-free survival among patients in subgroups defined according to the presence or absence of high-risk features was also assessed. These features included extramedullary disease and a β\u003csub\u003e2\u003c\/sub\u003e-microglobulin level of at least 5.5 mg per liter.\u003c\/p\u003e\n\n\u003ch2 id=\"product\"\u003eHow Anito-cel Behaves in the Body\u003c\/h2\u003e\n\n\u003cp\u003eAnito-cel infusion products showed high cell viability. The median CAR positivity was 72%. There was low interpatient variability in CAR expression per cell, with a median of 2.2 vector copies per cell. The yield was high.\u003c\/p\u003e\n\n\u003cp\u003eAfter a single infusion, anito-cel underwent robust expansion in all patients. A median maximum peak expansion of 139,000 copies per microgram of genomic DNA (range, 10,100 to 686,000) was observed at a median of 13 days (range, 8 to 59). This corresponds to a median of 22,000 copies per microgram in peripheral blood (range, 2 to 10,868).\u003c\/p\u003e\n\n\u003cp\u003eThe median area under the curve between the day of infusion and day 28 was 1,240,000 copies per microgram of genomic DNA×days (range, 80,500 to 8,980,000). CAR transgene levels decreased to baseline levels by month 3. CAR was detectable at month 24 in one patient.\u003c\/p\u003e\n\n\u003cp\u003eThe median maximum peripheral expansion was 175,000 copies per microgram of genomic DNA (range, 10,068 to 686,000) among patients who received dexamethasone for the management of cytokine release syndrome. It was 95,918 copies per microgram of genomic DNA (range, 17,550 to 351,000) among those who did not.\u003c\/p\u003e\n\n\u003cp\u003eThe median peak absolute lymphocyte count was 1390 cells per microliter (range, 270 to 13,180) among patients treated with dexamethasone. It was 1010 cells per microliter (range, 350 to 3280) among those not treated with dexamethasone. The peak absolute lymphocyte count exceeded 10,000 cells per microliter in two patients (5%).\u003c\/p\u003e\n\n\u003cp\u003eNo patients had non-ICANS neurotoxic effects or immune-mediated colitis. This result suggests that an elevated absolute lymphocyte count alone is insufficient to induce these toxic effects.\u003c\/p\u003e\n\n\u003cp\u003eAnito-cel treatment led to robust tumor clearance. This was indicated by a reduced level of soluble BCMA starting on day 7. The level reached a nadir at a median of 88 days (range, 53 to 670) and then rebounded toward normal levels in most patients.\u003c\/p\u003e\n\n\u003cp\u003eThe median level of soluble BCMA at screening was 330 ng per milliliter (range, 39 to 4331) among patients who received dexamethasone for the management of cytokine release syndrome. It was 114 ng per milliliter (range, 29 to 503) among those who did not.\u003c\/p\u003e\n\n\u003cp\u003eLevels of proinflammatory cytokines and chemokines increased rapidly after the anito-cel infusion. They peaked at day 5 for interferon-γ (range, 2 to 32 pg per milliliter), at day 3 for interleukin-2 (range, 2 to 29 pg per milliliter), and at day 8 for interleukin-6 (range, 3 to 29 pg per milliliter). All of these peaks preceded peak anito-cel expansion. Most cytokine levels returned to preinfusion levels by day 28.\u003c\/p\u003e\n\n\u003cp\u003eAmong patients with a relapse after the anito-cel infusion, post hoc analyses indicated that CAR T cells were undetectable on the basis of vector copy number. This was despite measurable levels of soluble BCMA in all but one patient at the time of disease progression.\u003c\/p\u003e\n\n\u003ch2 id=\"lab\"\u003eLaboratory Comparison: ddBCMA vs. Dual-VHH Binders\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers compared the ddBCMA binder used in anito-cel with the dual-VHH binder used in cilta-cel in laboratory studies. The ddBCMA binder had a faster off-rate than the dual-VHH binder.\u003c\/p\u003e\n\n\u003cp\u003eAlthough cytotoxicity was similar with the two therapies, ddBCMA CAR T cells led to less cytokine release. The ddBCMA CAR T cells also did not result in activation without antigen. They did not cause off-target cytotoxic effects.\u003c\/p\u003e\n\n\u003cp\u003eThese laboratory findings may help explain the clinical safety profile observed with anito-cel. The faster off-rate and reduced cytokine release may contribute to the low rates of severe cytokine release syndrome and ICANS seen in the study.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eClinical Implications: What This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eAnito-cel therapy led to a high incidence of response among patients with heavily pretreated relapsed or refractory multiple myeloma. All 38 patients (100%) had a response, and 79% had a complete response.\u003c\/p\u003e\n\n\u003cp\u003eThe safety profile was notable for rare grade 3 or higher cytokine release syndrome and ICANS. Among patients who received the recommended phase 2 dose of 100×10\u003csup\u003e6\u003c\/sup\u003e CAR+ T cells, 94% had cytokine release syndrome of grade 1 or 2. No patients at this dose had grade 3 or higher cytokine release syndrome.\u003c\/p\u003e\n\n\u003cp\u003eA total of 16% of patients at the recommended dose had ICANS of grade 1 or 2, and 1 patient (3%) had a grade 3 event. No non-ICANS or delayed neurotoxic effects occurred. Specifically, there were no cases of parkinsonism, cranial-nerve palsies, Guillain–Barré syndrome, or colitis.\u003c\/p\u003e\n\n\u003cp\u003eThese findings are important because rare but irreversible neurotoxic effects have been reported with other BCMA-directed CAR T-cell therapies. The absence of these effects with anito-cel in this study suggests that the ddBCMA binder design may offer a safety advantage.\u003c\/p\u003e\n\n\u003cp\u003eThe median progression-free survival was 30.2 months, and the 24-month progression-free survival was 57%. The 36-month overall survival was 65%. Among patients who had a sustained MRD-negative status for at least 12 months, no patient had progression or death through 33 months after the anito-cel infusion.\u003c\/p\u003e\n\n\u003cp\u003eThe dose-expansion cohort proceeded with dose level 1 (100×10\u003csup\u003e6\u003c\/sup\u003e CAR+ T cells). This dose was subsequently selected for phase 2 testing in the iMMagine-1 trial.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations: What the Study Could Not Prove\u003c\/h2\u003e\n\n\u003cp\u003eThis was a phase 1 study. Phase 1 studies are designed primarily to assess safety and to find the recommended dose for further testing. They are not designed to prove that a treatment is better than another treatment.\u003c\/p\u003e\n\n\u003cp\u003eThe study was not designed for hypothesis testing. Because of this, confidence intervals are descriptive and were not adjusted for multiplicity. This means the results should be interpreted with caution.\u003c\/p\u003e\n\n\u003cp\u003eThe size of the expansion cohort reflected clinical and operational considerations rather than formal statistical power. A cohort size of approximately 26 patients was deemed adequate to characterize safety and estimate preliminary activity at the recommended dose. This is a relatively small number of patients.\u003c\/p\u003e\n\n\u003cp\u003eThe median follow-up was 38.1 months. Longer follow-up is needed to assess the durability of responses and long-term safety.\u003c\/p\u003e\n\n\u003cp\u003eTwo patients did not undergo infusion owing to infection and to heart failure–induced hypoxia. This means the safety and efficacy results apply only to patients who were able to receive the infusion.\u003c\/p\u003e\n\n\u003cp\u003eSecondary primary myelodysplastic syndrome was reported in 3 of 38 patients (8%). These events occurred in the context of disease progression and after exposure to cytotoxic chemotherapy. The investigators assessed the events as being unrelated to anito-cel. However, the possibility of a relationship cannot be completely ruled out.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Next Steps\u003c\/h2\u003e\n\n\u003cp\u003eAnito-cel is an investigational therapy. It is not yet approved for general use. Patients interested in this treatment should discuss clinical trial options with their healthcare team.\u003c\/p\u003e\n\n\u003cp\u003eThe recommended phase 2 dose was established as 100×10\u003csup\u003e6\u003c\/sup\u003e CAR+ T cells. This dose was selected because the safety and efficacy profiles were similar to those observed with the higher dose, and the manufacturing success was 100%.\u003c\/p\u003e\n\n\u003cp\u003eDose level 1 was subsequently selected for phase 2 testing in the iMMagine-1 trial. This trial will provide more information about the safety and efficacy of anito-cel in a larger group of patients.\u003c\/p\u003e\n\n\u003cp\u003ePatients considering CAR T-cell therapy should be aware of the potential side effects. These include cytokine release syndrome and ICANS. In this study, these side effects were mostly low grade and manageable with tocilizumab and dexamethasone.\u003c\/p\u003e\n\n\u003cp\u003ePatients should also be aware that hypogammaglobulinemia (low levels of protective antibodies) occurred in 32% of patients during the treatment period. Infection of any grade occurred in 55% of patients, with 16% having infection of grade 3 or higher. Monitoring for infections is important after CAR T-cell therapy.\u003c\/p\u003e\n\n\u003cp\u003eThe study authors concluded that anito-cel therapy led to a high incidence of response among patients with heavily pretreated relapsed or refractory multiple myeloma. Cytokine release syndrome and ICANS of grade 3 or higher were rare.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is anito-cel and how does it work?\u003c\/h3\u003e\n\u003cp\u003eAnito-cel is an investigational CAR T-cell therapy made from a patient's own T cells, which are modified to target BCMA on myeloma cells. Its binder, ddBCMA, is designed to attach and release quickly and not clump together, aiming to kill tumor cells while producing fewer inflammatory cytokines.\u003c\/p\u003e\n\u003ch3\u003eIs anito-cel approved, and how can patients access it?\u003c\/h3\u003e\n\u003cp\u003eAnito-cel is investigational and not yet approved for general use. Patients interested in this treatment should discuss clinical trial options with their healthcare team. The recommended phase 2 dose was 100×10⁶ CAR+ T cells, and this dose is being tested in the iMMagine-1 trial.\u003c\/p\u003e\n\u003ch3\u003eWhen should a patient with relapsed or refractory multiple myeloma seek a second opinion about CAR T-cell therapy?\u003c\/h3\u003e\n\u003cp\u003eAnito-cel is an investigational BCMA-directed CAR T-cell therapy, not yet approved for general use, and the phase 1 data come from 38 heavily pretreated patients, all of whom had a response and 79% a complete response, with median progression-free survival of 30.2 months. Because the trial was not designed to prove one treatment is better than another, and longer follow-up is needed, a second opinion can help clarify whether a clinical trial, an approved BCMA-directed CAR T-cell therapy, or another option fits your situation. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Phase 1 Study of Anito-cel, a d-Domain BCMA CAR T Cell for Refractory or Recurrent Myeloma\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e M.J. Frigault, B. Dhakal, A.J. Jakubowiak, N. Raje, K. Banerjee, C.J. Mu, K.C. Hart, S. Shachar, L.P. Andrews, L.S. Cheung, F.M. Griffin, A.R. Witter, M. Hyde, C. Pham, N. Gandra, T. Shakya, B. Rajan, C. Cortesio, S.T. Haile, H. Nowyhed, P. Nair-Gupta, P. Mitra, R.J. Chan, A. Kostic, C.R. Heery, J. Rosenblatt, and M.R. Bishop\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e \u003cem\u003eNew England Journal of Medicine\u003c\/em\u003e, 2026; volume 395, pages 1180-92\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1056\/NEJMoa2603527\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eClinicalTrials.gov number:\u003c\/strong\u003e NCT04155749\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c\/strong\u003e Arcellx and Kite, a Gilead company\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47807287263388,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-anito-cel-car-t-cell-therapy-for-relapsed-or-refractory-multiple-myeloma-a-patient-guide-to-the-phase-1-study-hero.png?v=1792041749","url":"https:\/\/diagnosticdetectives.com\/es\/products\/anito-cel-car-t-cell-therapy-for-relapsed-or-refractory-multiple-myeloma-a-patient-guide-to-the-phase-1-study","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}